Integrated genomic approaches to identify the molecular pathogenesis of schizophrenia

• Main Authors: Min-Chih Cheng, 鄭敏志
• Other Authors: Chia-Hsiang Chen
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/75133634106353627105

博士 === 慈濟大學 === 醫學研究所 === 98 === Schizophrenia is a common psychiatric disorder with a prevalence of approximately 1 % of the general population worldwide (0.3~1 % in Taiwan) and is characterized by psychotic symptoms such as hallucinations, delusions and bizarre behaviors. Despite a high heritability of about 80 %, the major genetic components underlying the disease’s susceptibility and pathology have remained elusive. Aripiprzole is an antipsychotic drug, while methamphetamine (MAP) is a psychotomimetic drug that can induce psychotic symptoms in human. Using cDNA microarry, we found that the Egr1, Egr2 and Egr4 genes were up-regulated in the rat frontal cortex under chronic treatment of aripiprazole. In the pharmacological model of psychosis, we detected increased expression of the Egr1 and Egr3 proteins in the mouse hippocampus after 4 weeks’s administration of methamphetamine (MAP, 1 mg/kg/day), and increased expression of Egr1 and Egr4 proteins in the mouse hippocampus after 4 weeks’s treatment with MK-801 (0.5 mg/kg/day), respectively, suggesting EGR protein family might be involved in the moelcular mechanism of antipsychotic and psychotomimetic drugs. In further genetic association studies between the EGR family genes and schizophrenia in Han Chinese samples from Taiwan (564 patients and 564 control subjects), we found a significant over-representation of the C/C homozygotes of the rs9990 of the EGR2 gene in female patients compared to female controls. Western blot analysis also showed a significantly higher EGR2 protein level in the lymphoblastoid cells of female patients than that in the female control subjects. In addition, we also detected an association of the EGR4 gene with male schizophrenia in this study. There were significant over-representations of the T/T homozygotes of the rs6747506, the A/A homozygotes of the rs6718289, the T/T homozygotes of the rs2229294, and the A/A homozygotes of the rs3813226 in male schizophrenia patients as compared to male control subjects. Reporter gene assay revealed that the haplotype T-A (rs6747506- rs6718289) had significantly lower promoter activities than A-G, indicating that lower EGR4 activity is associated with schizophrenia. In summary, our data suggest that EGR protein family might be involved in the pathogenesis of schizophrenia.